Obesity is a major public health problem affecting over 30% of the US population. In addition to its negative consequences on the rest of the body, obesity is associated with profound neural and cognitive deficits. The long-term objectives of this proposal are to determine the cellular underpinnings of obesity-induced cognitive dysfunction with the ultimate goal of developing novel interventions. Neuroimaging studies have shown that obese humans exhibit decreases in the volume of brain regions supporting higher level cognition, including the prefrontal cortex. In a rodent model of diet-induced obesity, simila findings have been observed, as well as the loss of dendritic spines, primary sites of excitatory synapses, and synaptic proteins. In addition, obesity increases the numbers of microglia in brain regions involved in cognition. Because microglia are known to phagocytose neuronal debris under conditions of disease and damage, a traditional interpretation of these findings is that the increased numbers of microglia in the obese brain facilitate clearance of degenerating synapses. However, developmental studies showing that microglia play an active role in sculpting neural circuitry suggest an alternative possibility: that microglial phagocytosis of synapses is a cause rather than an effect of synaptic loss in obesity, and a contributor to cognitive decline. The focus of this exploratory proposal is to test this hypothesis. First, diet-induced obesity in wildtype and transgenic mice along with immunolabeling, western blots, DiI labeling, electron microscopy and behavioral tasks will be used to determine whether microglial engulfment of synapses is associated with cognitive decline. Second, blockers of microglial activation and microglial phagocytosis combined with the above methods will be used to examine whether microglia are responsible for synapse loss and cognitive decline. Taken together, these experiments will explore the relationship between microglia and synapse loss and help elucidate mechanisms underlying obesity-induced cognitive dysfunction.